Trifluoromethyl-substituted alcohols of formula (I) have been described as ligands that bind to the glucocorticoid receptor. These compounds are effective as therapeutics in treating a number of diseases modulated by glucocorticoid receptor function, including inflammatory, autoimmune and allergic disorders. Examples of these compounds are described in U.S. patent application Pub. Nos. 2003/0232823 (corresponding to PCT International Publication No. WO 03/059899), 2004/0029932 (corresponding to PCT International Publication No. WO 03/082787), and 2004/0023999 (corresponding to PCT International Publication No. WO 03/082280), which are each incorporated herein by reference in their entireties and are hereinafter termed “the Trifluoromethyl-Substituted Alcohol Patent Applications”.

It is well known in the art that enantiomers of a particular compound can have different biological properties including efficacy, toxicity, and pharmacokinetic properties. Thus, it is often desirable to administer one enantiomer of a racemic therapeutic compound.
The synthetic methods disclosed in the patent applications cited above describe the synthesis of racemic products. Separation of enantiomers was accomplished by chiral HPLC and may be accomplished by other conventional ways of separating enantiomers. Chiral HPLC and other enantiomer separation method, however, are generally unsuitable for large-scale preparation of a single enantiomer. Thus, a stereoselective synthesis for preparation of these compounds would be highly desirable.
The present invention discloses a stereoselective synthesis of certain compounds of formula (I). The key step involves a novel, chiral auxiliary controlled addition of trifluoromethide ion, generated from trifluoromethyltrimethylsilane (TMS-CF3) and fluoride ion, to a keto-ester. There are no examples of chiral auxiliary controlled CF3 addition to carbonyl groups in the chemical literature. One report describes the stereoselective addition of trifluoromethide ion to α,β-unsaturated N-tert-butanesulfinimines to prepare trifluoromethylated allylic amines (G. K. Surya Prakash et al., Org. Lett., 2001, 3, 2847).
P. Ramaiah and G. K. Surya Prakash (Synlett, 1991, 9, 643) describe the preparation of racemic 2-hydroxy-2-(trifluoromethyl)alkanoic esters by addition of trifluoromethide ion generated from TMS-CF3 and fluoride ion to α-ketoesters. K. Iseki et al. (Tetrahedron Lett., 1994, 35, 3137) describe the asymmetric trifluoromethylation of aldehydes and ketones with TMS-CF3 in the presence of catalytic chiral quaternary ammonium fluorides. Enantiomeric excesses between 15% and 51% were reported. This method was found to be unsuitable for our substrate, proceeding very sluggishly and giving less than 1% conversion. T. Hagiwara et al. (Main Group Chem, 1997, 2, 13) demonstrated addition of CF3 to aldehydes in 9% enantiomeric excess by reaction with TMS-CF3 in the presence of a chiral Lewis base catalyst (quinine). No reaction was observed, however, when this system was applied to our substrate of interest.